6-aza-3h-1,4-benzodiazepines

ABSTRACT

There are prepared compounds of the formula:   WHEREIN: N IS AN INTEGER FROM 1 TO 4; R1 is alkyl of 1 to 6 carbon atoms, a hydroxy group, an amino group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenyl group substituted with alkyl of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, trifluoromethyl, fluorine or chlorine; A is oxygen, sulfur, the imino group, or an alkylimino group having 1 to 6 carbon atoms, or when R1 is phenyl or substituted phenyl A also is two alkoxy groups having 1 to 6 carbon atoms or alkylenedioxy with 2 to 4 carbon atoms or -C(R1) A is the cyano group; B is oxygen, sulfur, an imino group or an alkylimino group having 1 to 6 carbon atoms; R2 is hydrogen, a hydroxy group, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, or the group -O(CH2)n-C( A)-R1; No is nitrogen or an NO group; and R3 and R4 are the same or different and are hydrogen, chlorine, fluorine, the trifluoromethyl group, alkyl groups of 1 to 6 carbon atoms or alkoxy groups with 1 to 6 carbon atoms, the tautomeric forms thereof and pharmaceutically acceptable salts thereof. The compounds have psychosedative, anxiolytic, spasmolytic, antipsychotic and antiphlogistic activity.

United States Patent [1 von Bebenburg et al.

11 3,900,466 Aug. 19, 1975 i 5 G-AZA-SH-l ,4-BENZODIAZEPINES [73] Assignee: Deutsche Goldund Silber-Scheideanstalt vormals Roessler, Germany [22] Filed: May 8, 1974 21] Appl. No.: 468,088

[30] 3 Foreign Application Priority Data 7 May 25, 1973 Austria 4628/73 [56] References Cited UNITED STATES PATENTS 4/1967 Littell et a1 260/2393 B Fri/nan Exanziner--Henry R. Jiles Assistant ExaminerRobert T. Bond Attorney, Agent, or Firm-Cushman, Darby & Cushman ABSTRACT There are prepared compounds of the formula:

((IIH c R /,-"B N C 4 I CH R C N wherein:

n is an integer from 1 to 4;

R is alkyl of 1 to 6 carbon atoms, a hydroxy group, an amino group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenyl group substituted with alkyl of l to 6 carbon atoms, an alkoxy group of l to 6 carbon atoms, trifluoromethyl, fluorine or chlorine;

A is oxygen, sulfur, the imino group, or an alkylimino group having 1 to 6 carbon atoms, or when R is phenyl or substituted phenyl A also is two alkoxy groups having 1 to 6 carbon atoms or alkylenedioxy with 2 to 4 carbon atoms or C(R )=A is the cyano group;

B is oxygen, sulfur, an imino group or an alkylimino group having I to 6 carbon atoms;

R is hydrogen, a hydroxy group, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, or the group N,, is nitrogen or an NO group; and

R and R are the same or different and are hydrogen, chlorine, fluorine, the trifluoromethyl group, alkyl groups of l to 6 carbon atoms or alkoxy groups with l to 6 carbon atoms, the tautomeric forms thereof and pharmaceutically acceptable salts thereof. The compounds have psychosedative, anxiolytic, spasmolytic, antipsychotic and antiphlogistic activity.

12 Claims, N0 Drawings The present invention is concerned with new 6-aza-3-H-l ,4-benzodia'zepines of the formula:

whereinf I n is an integer from 1 m4; R, is alkyl of l to 6 carbon atoms, a hydroxy group,

an amino group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenyl group substituted with alkyl of l to 6carbon atoms, an alkoxy group of l to 6 carbonatoms, trifluoromethyl, fluorine or chlorine; I u A is oxygen, sulfui, the imino groups, or an alkylimino group having I to 6 carbon atoms, or when R, is phenyl or substituted phenyl, A also is two alkoxy groups having 1 to 6 carbon atoms or alkylenedioxy'with 2 to 4 carbon atoms or C(R )=A is the cyano group B is oxygen, sulfur, an imino group or an alkylimino group having 1 to 6 carbon atoms; 1 R is hydrogen, a hydroxy group, an alkyl group with l to 6 carbon atoms, an alkoxy group with l to 6 carbon atoms, or the group" O('CH C(=A- )R|Z N is nitrogen or an NO group; and R and R are the same or different and are hydrogen, chlorine, fluorine, the trifluoromethyl group, alkyl groups of l to 6 carbon atoms or alkoxy group with 'l to6carbon atoms, the tautomeric forms thereof and pharrnaceutically acceptable salts thereof. Preferably the alkyl group's alkoxy groups and alkylimino groups preferably have] to 4 carbon atoms. In the event R} is asubstituted' phenyl group it can be mono or di substituted and the substitutents can be the same or different. In the event that A is an alkylenedioxy group preferably it is the ethylenedioxy group, i.e., A with the attached carbon atom forms the dioxolane ring.

Examples of alkyl and ,alkoxy groups which can be present include methyLethyl, propyl, isopropyl, butyl, tert.buty|, sec. butyl, amyl, hexyL isobutyl, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, amyloxy, hcxoxy, propoxy. Examples of alkylimino groups are methylimino, ethylimino, propylimino, butylimino,

hexylimino, sec. butylimino.

The group --C(=B)--CHR,-- in a given case can also be present in the isomeric or tautomeric form --C(BR =CH i In addition to the compounds mentioned in the working examples the other compounds within the present invention include:

l-carbmethoxybutyl-5-phenyl-6-aza-7-chlorol ,2-

dihydro-3 H-l ,4-benzodiazepinone-( 2 l -carbopropoxyethyl-5-phenyl-6-aza-7-c hlorol ,2- dihydro-3 H- l ,4-benzodiazepinone-( 2- )-4-oxide; l-carbobutoxymethyl-S o-trifluoromethylphenyl 6-aza-7.-chlorol ,2-dihydro-3 H-l ,4- benzodiazepinone-( 2 l-carbohexoxyethyl-5-( 2,5-dichlorophenyl )-6-aza-7- chlorol ,2-dihydro-3 H- l ,4-benzodiazepinone-( 2); I -carboethoxyethylp fluorophenyl 6-aza-7- chlorol ,2-dihydro-3 H- l ,4-benzodiazepinone-( 2 l-carboisopropoxymethyl-5-( o-tolyl )-6-aza-7- chloro-l ,2-dihydro-3H- l ,4-benzodiazepinone-( 2 l-carboethoxymethyl-5-( 2-fluoro-4-methylphenyl 6-aza-7-chlorol ,2-dihydro-3H-l ,4 benzodiazepinone-( 2 l-carbomethoxyethyl-5-( o-t-butylphenyl )-6-aza-7- chlorol ,2-dihydro-3H- l ,4-benzodiazepinone-( 2 l-carboethoxymethyl-5-( o-hexylphenyl )-6-aza-7- chlorol ,2-dihydro-3H l ,4-benzodiazepinone-(2 l-carboethoxyethyl-5-(o-methoxyphenyl )-6-aza-7- chlorol',2-dihydro-3H- l ,4-benaodiazepinone-( 2 l -carboethoxyethyl-S-(o-ethoxyphenyl )-6-aza-7- chlorol ,2-dihydro-3 H- l ,4-benzodiazepinone-( 2 l -carbomethoxymethyl-S-( o-butoxyphen yl )-6-aza-7- chloro-l ,2-dihydro-3H- l ,4-benzodiazepinone-( 2 l-carboethoxypropyl-S o-hexoxyphenyl )-6-aza-7- chloro-l ,2-dihydro-3H- l ,4-benzodiazepinone-( 2 l-carboethoxymethyl-3-methyl-5 -phenyl-6aza-7- chlorol ,2-dihydro-3 H- l ,4-benzodiazepinonc-( 2 l-carboethoxyethyl-3-isopropyl-5-(o-chlorophenyl 6-aza-7-chloro-l ,2-dihydro-3 H- l ,4- benzodiazepinone-( 2 l-carboethoxymethyl-3-butyl-5 o-fluorophenyl )-6- benzodiazepinone-( 2 l-carbornethoxyethyl-3-hexyl-5 m-chlorophenyl 6-aza-7-chloro-l ,2-dihydro-3H-l ,4- benzodiazcpinone-( 2 l-carboethoxymethyl-3:hydroxy-5-( 0- chlorophenyl )-6-aza-7-chloro-l ,2-dihydro-3 H- l ,4- benzodiazepinone-( 2 1 l -carboethoxyethyl-3-methoxy-5-phenyl-6-aza-7- chlorol ,2 dihydro-3H- l ,4-benzodiazepinone-( 2 l -carboethoxyethyl-3-ethoxy-5-( otrifluoromethylphenyl )-6-aza-7-chlorol ,2- dihydro- 3H- 1 ,4-benzodiazepinone-( 2 v l-carboethoxymethyl-3-butoxy-5-phenyl-6-aza-7- chlorol ,2-dihydro-3H- l ,4-benzodiazepinone-( 2 l -earbo"ethoxymethyl- 3-hexoxy-5-( ochloroophenyl )-6-aza-7-chlorol ,2-dihydro-3H- l,4-benzodiazepinone-(2);

with a compound of the formula:

1 Y-CH- CHR --NH, V

wherein R and B are as defined above and Y is a hydroxy group, a halogenatom, an alkoxy group, a mercapto group, an alkyl mercapto group, an amino group or an alkylamino group, in a given case with addition of an acid binding agent, or

- c. in a compound of formula I one or more of the symbols R R A and N can be'changed to give a compound of corresponding meaning.

Process (a') is carried out, in a given case with the addition of customary acid binding agents such as alkali carbonates,'e.g., sodium'carbonate or potassium carbonate, pyridine or other customary tertiary amines, e.g., triethyl amine, at temperatures between 0 and 150C. in inert solvents such as dioxane, dimethyl formamide, dimethyl sulfoxide, aromatic hydrocarbons such as benzene and toluene or acetone. It is also possible to proceed by first producing an alkali compound of the compound of formula ll which is to be reacted, by reacting the'compound of formula ll in an inert solvent such as dioxane, dimethyl formamidc, benzene or toluene with an alkali metal, alkali hydride or alkali amide (especially sodium, sodium hydride or sodamide) at temperatures between 0 and 150C. and then adding the compound of formula III.

Process (b) takes place in customary solvents or suspension media at temperatures between 0 and 200C., preferably to 150C. Especially there can be employed polar solvents, for example, alcohols, e.g., methyl alcohol, ethylalcohol, propyl alcohol, isopropyl alcohol and butyl alcohol, dioxane, tetrahydrofurane, dimethyl sulfoxide, dimethyl formamide or imidazole, as well as media such as pyridine or quinoline. In case Y is a halogen atom itcan be advantageous (but otherewise there should not be added) to add basic materials', e.g.,-sodium hydroxide, which facilitate an acid splitting. In case Y is a hydroxy group it is suitable and,

sometimes necessary to add customary water splitting off "(dehydrating) agents such as dicyelohexylcarbodiimide or l-ethoxy-2-carbethoxy-l.2- dihydroquinoline. In case Y is alkylmercaptogroup, alkoxy group or alkylamino group these groups are preferably; of lower molecular weight and for example consist of l to 6 carbon atoms, e.g., methyl mcrcato, hexyl mercapto, methoxy, ethoxy, methylamino and hexyl ar'ninoj v Frequently process (b) can also be carried out in such manner that the amino group in the 3-position of formula IV and/or the amino group of formula V (Y=NH carries a protective group known in itself. Frequently such protective groups are already required for the production of the starting compounds. In many cases the splitting off of such a protective group takes place simultaneously with the cyclization.

These protective groups are easily split off. There are employed either easily solvolytically splittable acyl (potash,v soda, aqueous alkali solutions, alcoholic alkali solutions, N a) at room temperature or with a short boiling. Hydrogenizably splittable groupssuch as the benzyl group or the carbobenzoxy radical are suitably split off by catalytic hydrogenation in the presence of customary hydrogenation catalysts, especially palladium catalysts, in'a solvent or suspension agent, in a given case under elevated pressure. As solvents or suspension agent there can be used water, lower aliphatic alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers, e.g., diethyl ether,

dimethyl formamide, etc. as well as mixtures of these materials.

As protective groups for the amino group there can be used for example, the benzyl group, a-phenylethyl group, benzyl groups substituted in the benzene nucleus as for example, the p-bromo or p.-nitrobenzyl group, the carbobenzoxy group, the carbobenzthio group, the trifluroacetyl, the phthalyl radical, the trityl radical, the p-toluenesulfonyl radical and similar groups as well as simple acyl groups such as the acetyl group, formyl group, tert. butylcarboxy group, etc. There can be employed especially the protective groups used in the synthesis of peptides and the splitting processes customarily employed in that process. Among others for this purpose reference is made to Jesse P. Greenstein and Milton Winitz Chemistry of Amino Acids", John Wiley and Sons, Inc.,' New York (1961), Vol.2, pages 883 et seq. Also there canbe used carboalkoxy groups (for example of lower molecular weight such as carbmethoxy, carbethoxy and carbpropoxy).

Process (b) can also be carried out under some circumstances so that before the true cyclization there is prevously isolated the intermediate product of the formula:

out the cyclization in an aromatic hydrocarbon, e.g., benzene or toluene, with addition of a tertiary amine,

e.g., triethyl amine or pyridine.

7 According to porcesstc) azabenzodiazepinc 1 formula I can be reacted further or substituted in a suitable manner.:For example, compounds of formulal wherein R is an OH group can be esterified ina suitable manner. For this-purpose there canbe used for 'example lower aliphatie alcohols, e.g., of l to 6 carbon .atoms such as methyl alcohol, ethyl alcohol, isopropyl alcohol, propyl alcohol,--butyl alcohol,.sec. butyl alcohol, t-butyl alcohol, amylalcohol, or hexyl alcohol, in the presence of-acid catalysts, e.g., hydrochloric acid, sulfuric acid or p-toluene sulfonic acid or there can be reacted diazoalkanes having l to'6 carbon atoms, e.g., diazomethane and .diazohexane, in the conventional manner in ethereal of dioxane solution at temperatures between and 50C. a v

The groups Aand B in compounds of formula I can be changed-by various procedures. Thus, ,in case A and B are oxygen, theseatoms can be-replaced by a sulfur atom by means of phosphorus pentasulfide. This reaction takes place in inert solventssuch as-benzene, toluene, dioxane, pyridine,v of chlorohydrocarbons,.-e.g,, chloroform, at temperatures between 0 and 150C. Compounds in whichA and/or B- isoxygen; or sulfur can in turn be reacted in polar mediatsuch as those mentioned above, for example). withjammonia alkylamines with' l to 6 carbon .atoms,- e.g,, methylamine, ethyl amine, propyl amine, isopropyl amine, butyl amine, amyl amine or hexyl amine to form compounds in which A and/or'B are imi'no or. alkylimno groups. The reactions are carried out for example in polar.solventssuch as methanol, ethanolor excess amine at temperatures. between 0-and 150 C. lg

In case A is two alkoxy grups or an alkylenedioxy group (inwhichR, isphenyl min a given case substituted phenyl) there can be obtained therefrom the ketone where A is 0 in a manner known in itself using acid conditions. This reaction is carried out for example in polar solvents or suspension media which contain some water, as well as in aqueous methanol, ethanol, dioxane or tetrahydrofurane with the addition of some aqueous hydrochloric acid, sulfuric acid, p-toluene sulfonic acid, etc., or it can also be carried out in aqueous media. The temperature is between 0 and 100C, prefer- :ably at 0 to C.

water free hydrochloric acid, sulfuric acid or p-toluene sulfonic acid, in a given case with azeotropic distillation off of the water formed in the reaction. The temperatue employed are between 0 and 160C, preferably 50 to C. -z' r .Compounds ofnformula l in which R is an alkyl group, an alkoxy or the group -.O(CH ,C(=A) f R, can be produced from compounds of formulal in which R, is H or OH by alkylation, For example,'th e alkylation takes place by reaction with esters of the formula HalR, SO (ORT) or ArSO OR','-, wherein HaLis a halogen atom, especially Cl, Br or I, Ar is an aromatic radical (especially a phenyl or naphthyl radicaLfin a given case substituted by one or more lower alkyl groups) and R? is an alkyl group with l to 6 carbon atoms or the groups --.(CH C A) R Examples are p-toluenesulfonic ac d ethyl, esters. e.g., methyLp-tolucnesulfonate', ethyl-p-toluenesulfonate, lower dialkyl sulfates, e.g., dimethyl sulfate and diethyl sulfate and the like. The alkylation reaction takes place, in a given case, with addition of customary acid potassium carbonate, pyridine or other customary tertiary amines at temperatures between 0 and C. in inert solvents such as alcohols, e.g., methyl alcohol, ethyl alcohol or. propyl, alcohol, dioxane, dimethyl formamide, dimethyl sufloxide, aromtiehydrocarbons such as benzene or toluene or acetone as well as mixtures of such solvents, I I

For alkylation with alkyl halides- (for example, iodides) in the'presence of NaH it has beenfound favorable to react in a mixture of :toluene and a little dimethyl formamide (O.l. to 5,%, for example 0.5%). ;In the alkylation it can alsoibe provided that ,the c0mpound of'formula -l.-in w hi ch R is H or OH.,can firstbe converted to an alkalicompound if it is treated with an alkali metal, alkali'hydride or, alkali amide (especially sodiumorsodium compounds such as sodiumhydride and sodamide) in an inert solvent such as dioxane, dimethylformamide, benzene or toluene at temperatures between 0 and-1509C. ,and then the alkylating agent added. g y I Compunds; of formula'l'wherein N is a nitrogen atom cambe convertedinto the corresponding N -oxide, For

this purposecompoundsinwhich N is ahitrogen atom are reacted with hydrogemperoxide, paracetic acid or other customary peracids in inert solvents such as clilute acid, ,ethyl acetate or acetone. The temperature employed is preferably between-0,and 50C,.

- Conversely in compounds of formulal wherein N is the group, NO thevoxygen atom can beremoved by catalytic hydrogenation or by chemical deoxygenation. As catalysts for the catalytic hydrogenation there ,are

suitable, for example, the customary metallic hyd rogenation. catalysts, especially nob'le metal, catalysts (palladium/activated .carbom, platinum) or Raneynickel; as solvents there are preferably, employed lower alcohols, e,g., methanol, ethanol and isopropanol. The

temperatures employed. are between 0.and 200 C apreferablybetween 0 andJQOfC. In, a given caseithe ,process .can be carried outat pressures up to 5 0;atmospheres absolute., For chemical deoxygenatioh there salts therecanbe employedthe known and therapeutically usable (pharmacologically'acdeptable) acid residues, For example therecan be used acids such as sulfuric,;acid,,phosphoric acid, hydrohalic'v acids, e.g., hy-

drochloric acid or hydrobromic acid, ethylenediamine tetraacetic acid, sulfamic,acid,.benzene sulfonic acid, p-toluene, sulfonic acid, ,camphor sulfonic ,acid, emthane sulfonic acid, guarazulenesulfonic acid, maleic 'acid, furnaric acid, oxalic, acid, tartaric acid, lactic acid,

H citric acid, ascorbic acid, glycolic acid, salicylic acid,

I acetic acid,propionic acid, gluconic acid, benzoic acid,

acetamidoacetic acid, hydroxyethane sulfonic acid, malonic acid.

v if the compoupds of formula l contain acid groups they can be converted in customary manner into their alkali (e.g., sodium or potassium ammonium or subtreating a solution in an organic agent such as alcohols,

e.g., methanoL with soda or soda lye. Those compounds of formulal which contain asym metric carbon atoms and as a rule result as race'ma'te's', can be split into the optically active isomers in known manner with the'help of an optically active acid. However, it is also possible to employ from the beginning an optically active starting material whereby a correspondingly optically active or diastereomer form is obtained as the end product.

The compounds of the invention are suitable for the production of pharmaceutical compositions. The pharmaceutical compositions or medicaments can contain one or more of the compounds of the invention or mixtures of the same with other pharmaceutically active materials. For the production of pharmaceutical preparations there can be used the customary pharmaceutical carriers and assistants. The medicines can be employed entcrally, parenterally, orally or perlingually. For example, dispensing can take place in the form of tablets, capsules, pills, dragees, plugs, salves, jellies, cremes, powders, liquids, dusts or aerosols. As liquids there can be used for example, oily or aqueous solutions or suspensions, emulsions,'injectable aqueous and oily solutions or suspensions:

For example there can be made and used in the invention compounds of formula I wherein the symbols n, A, .N,, and R to R have the following meanings:

n is l to 3 A is oxygen; I

N is nitrogen;

R1 is methoxy, ethoxy, propoxy, phenyl, fluorophenyl or chlorophenyl; v

, R is hydrogen orhydroxy;

R is hydrogen, fluorine,,or chlorine, preferably ,in

' the ortho position;

R is hydrogen. 3 The starting compounds used in process (a) can' be prepared for example according to the process of German published Application No. 2,259,471 or von Bebenburg et al. U.S. application Ser.-No. 313,542, filed Dec. 8, l972 orin analogousmanner to those processes. The entire disclosure of the von Bebenburg et al. U.S. application is hereby incorporated by reference. These starting compounds are claimed as new compounds in said von Bebenburg et al. application.

The starting compounds used in process (b) for example can be made from compounds of formula IV which contain a hydrogen atom in place of the group (CH C(=A)-R, (see German published application No. 2,259,471 ,and the von Bebenberg U.S. application Ser. No. 313,542) by alkylation with a compound of the formula Hal- (CH A)R,, wherein Hal is a chlorine or bromine using the conditions given in those two applications.

Unless otherwise indicated, all percentages are by weight.

gEXAMP LEl l-carbethoxymethyl-5-phenyl 6-a2a 7-chloro-l ,2-

dihydro-3H-l ,4-benzodiazepinone-( 2) 2 COOCZH To a solution of 27 grams (0.1 mole)of 5-phenyl-6- aza-7-chlorol ,2-dihydro-3 H-l ,4-benzodiazepinone- (2) (prepared as described in Example I of von Bebenberg application 3 l 3,542) in 250 ml of dimethyl formamide there were added 3.5 grams of sodium hydride (80% in white oil) at 20C. and then the mixture stirred for 30 minutes. Then there were dropped in 13 ml of ethyl bromoacetate whereupon an exothermic reaction occurcd and the temperature increased to C. The mixture was'stirred for another 30 minutes at 40 to C, then there were dropped in 50 "'m1 of ethanol and 20 ml of glacial acetic'acid and the'mixture poured into 1 liter of water. The substance cry'st allizin g out was filtered off with suction and recrystallized from'methyl ethyl ketone. g 4

Yield 20 gra ts; M.P. 184 to 186C.

EXAMPLE 2 l-a-carboxyethyl-5-phenyl-6 aia 7 -chloro-l dihydro -3H-l ,4-benzodiazepinone-( 2) c11 coon ophenone added. The temperature increased in 30 minutes to 40C. The mixture was stirred further for 1 hour, the dimethyl formamide distilled off in a vacuum and then residue dissolved in water. The solution was decolorized with activated carbon, then' acidified with glacial acetic acid. The oily product which precipitated crystallized in rubbing. It was recrystallized from chloroform/gasoline. M.P. l98202C.; Yield 14 grams.

EXAMPLE 3 l-[ 3-cyanopropyl-( l )]--phenyl-6-aza-7-chloro-l ,2- dihydro-3H- l ,4-benzodiazepinone-( 2) THZ CH2 CN T O N' C I z C1 N cr-N Into a mixture of 27 grams of 5-phenyl-6-aza- 7ehlorol ,2-dihydro-3H- l ,4-benzodiazepinone-( 2), 200 ml dioxane and 5 ml of dimethyl formamide there were introduced with stirring in a nitrogen atomosphere 4.5 grams of sodium hydride (57% in white oil). The temperature was increased to 30C. then the mixture was heated to 90C. and there were dropped in grams of gamma-bromobutyronitrile. The mixture was stirred for 5 hours at 9095C., then the inorganic salt was filtered off with suction and the filtrate evaporated in a vacuum. The syrupy residue was dissolved in 400 ml of chloroform, was washed 3 times with 5% aqueous sodium hydroxide and twice with water, the chloroform layer dried and treated with gasoline up to turbidity. The product in pure form crystallized out overnight. M.P. l70l74C.; Yield grams.

EXAMPLE 4 l-benzoylmethyl-5-( o-chlorophenyl- )-6-aza-7-ehlorol,2-dihydro-3H- l ,4-benzodiazepinone-( 2)-4-oxide To a mixture of 16.1 grams (0.05 mole) of 5-(ochlorophenyl )-6-aza-7- l ,2-dihydro-3H- l ,4-bcnzodiazepinone-4-oxide (made in a manner analogous to that used in von Bebenburg application No. 313,542 Example 3 for preparing 5-phcnyl-6-aza-7-chloro-l,2- dihydro-3H-l ,4-benzodiazepinone-( 2)-4-oxide but starting from 2-o-chlorobenzoyl-3-amino-6- chloropyridine), 200 ml of dioxane and 20. ml of dimethyl formamide there were added with stirring under a nitrogen'a'tmosphere at room temperature 1.7 grams of sodium hydride in white oil). Then there were added 8.6 grams of phenaeetyl chloride and the mixture stirred 4 hours at 50C. The product was separated by vacuum filtration from the precipitated salts. the filtrate acidified with glacial acetic acid and concentrated to one-third its volume in a vacuum. The residue crystallized. It was recrystallized from dimcthyl formamide/ethanol. M.P. 240C; Yield 15 grams.

EXAMPLE 5 l-benzoylmethyl-5-( o-chlorophenyl- )-6-aza-7-chlorol,2-dihydro-3H- l ,4-benzodiazepinone( 2) The title substance was prepared from 15.3 grams (0.05 mole) of 5-(o-chlorophenyl)-6-aza-7-chloro-l,2- dihydro-3H-l ,4-benzodiazepinone-(2) (prepared as set forth in Example 6 of von Bebenberg application No. 3l3,542)-in a manner analogous'to Example 4.

EXAMPLE 6 l-acetylmethyl-5-phenyl-6-aza-7-chloro-1,2-dihydro- 3H- l ,4-benzodiazepinone-( 2) CO CH To a mixture of 27 grams (0.1 mole) of -phenyl-6- aza-7-chlorol ,2-dihydro-3H- l benzodiazepinone- (Mi- 400 ml of dioxane and 40 ml of dimethyl formamide thcre were added under nitrogen with Stirring at EXAMPLE 7 l'-( 2-p-chlorophenyl-2-oxo-ethy l )-5 -phenyl-6-aza- 7- chlorol .Z-dihydrq-SH-l ',4-benzodiazepinone-( 2) To amixture of 27.2 grams (0. 1 mole) of 5-phenyl-6- aza-7-chloro- I ,2-dihydro-3H- l ,4-benzodiazeplinone- (2), 200 ml of dioxane and 25ml of dimcthyl formamidc there were added with stirring under nitrogen at C. 5 grams of sodium hydride (57% in white oil).

After 30 minutes there were added 25 grams of a,pv

dichloroacetophenonc and the mixture stirred for 2 hours at 50 C. The'dimethyl formamide was evaporated off in a vacuum, the'residuestirred up with water.

The crystals that formed were filtered off with suction and recrystallized from dimethyl formamid e/methanol.

Yield 30 grams; M.P. 2l6--2l8C.

. EXAMPLE 8 l-cyanom'ethyl-5-phenyl-6-aza-7-chlorol ,2-dihydro- 3H- 1 ,4-benzodiazepinonc-( 2) e11 CN v l3.5 grams (0.05 mole) of 5-phenyl-6-aza-7-chlorol,2-dihydro-3H-1,4-benzodiazepin0ne-(2) and 6 grams of chloroacetonitrile were reacted in a manner analogous to- Example 7. The reaction product was recrystal- Iize-d twice from acetone. Yield 6 grams; .M.P.

v EXAMPLE 9 l-carbethoxymethyl-5-phenyl-6-aza-7 chloro-l ,2- dihydro-ZH-l ,4-benzodiazepinone-( 2) This compound was made according to process (b) as follows:

grams of 2-benzoyl-3-[N-carbobenzoxyaminoacetyl )-N-carbethoxymethyl ]-amino-6-chloropyridine were introduced into 140 ml of a 40% solution of hydrogen bromide in glacial acetic acid, whereby the material dissolved with a strong development of gas. Then it was stirred for an additional hour and treated with 1 liter of ether. A thick oil precipitated and the upper layer decanted off. The'oil was dissolved in ml of methanol and made alkaline with aqueous ammonia, whereupon after a short time the desired product crystallized out. Yield: l4 grams; M.P. l84l86C.

The starting'material in Example 9 was produced as follows.

There were dropped into a solution of grams of 2-benzoyl-3-amino-6 chloropyridine in 250 ml of chloroform at room temperature 120 ml of trifluoroacetic anhydridel After the dying away of the exothermic reaction stirring was continued for 30 minutes and then 500 ml of gasoline (60 to 80C) added whereupon the 2-benzoyl-3-trifluroac etylamino-6-chloropyridine crystallized out. This was filtered off with suction andwashed with ethanol. Yield 124 grams; M.P. 134 to 66 grams (0.2 mole) of 2-benzoyl-3-trifluoroacetylamino-6-pyridine were dissolved in 500 ml of dimethyl formamide, then 10 grams of sodium hydridc (57% in white oil) added at room temperature and the mxture stirred for 30 minutes. Then there were droppedin 40 ml of ethyl bromoacetate and the mixture heated at 80 to 90C. with stirring for 5 hours. Thereupon there were dropped in 50 ml of ethanol, the solvent distilled off in a vacuum, the residue stirred with 400 ml of ethanol, a solution of 30 grams of potassium hydroxidein ml of water added and the mixture warmed for 30 minutes on the water bath with stirring. Upon cooling off the potassium salt of the acid began to crystallize out. The mixture was stirred with 3 liters of water and acidified with glacial acetic acid.

The precipitating crystals of the acid were filtc with suction and washed with water. Yield of 11,11 46 grams. The acid was esterified without further purification. For this purpose the 46 -grams of'acid were dissolved in 500 m1 of ethanol and there was introduced with stirring at 60C hydrogen chloride until saturation occurred. Next the solution was concentrated to 200 ml and cooled while stirring. Theprecipitated crystals of the Z-benzoyl-3 carbethoxymethylamino-ochloropyridine were filtered off with suction and washed with'ethanol. Yield 35 grams; M.P. 88to 90C.

Then 37 grams of carbobenzoxy-glycine were sudpended in 600 ml of diethyl ether and there were added with stirring at room temperature 40 grams of phosphorus pentachloride. The mixture was stirred for 30 min utes, whereupon everything went into solution. To this there were dropped in a solution of. 35 grams of 2- benzoyl-3-carbethoxymethylamin06chloropyridine in 100 ml of chloroform and the mixture boiled at reflux with stirring for l2 ,hours. The mixture was allowed to stand at room temperature for l day and night. Then the solution was shaken with ice water and thereafter with 5% aqueous sodium hydroxide solution and then again several times with water. The organic phase was dried and evaporated in a vacuum. The oil remaining behind, which mainly consisted of the 2-benzoyl-3-[-N (carbobenzoxyamino-acetyl )-N-carbethoxy-methyl amino-6-chloropyridine (still containing unreacted 2-benzoyl-3-earbethoxymethyl amino-6- chloropyridine) was added directly to the further reac-- tion as set forth above to produce the compound of Example 9. l a i The compounds of the invention are suited for the pr'oduetio'n of phafmaceutical compositions and prepa rations. The pharmaceutical compositions or drugs contain as the aetive material one or several of the compounds of the invention, in a given case in admixture with other" pharmacologicalllyor pharmaceutically effective materials. The production of the medicine can take place with the use of known and customary pharmaceutical assistants,carriers and diluents.

Such carriers and assistants as set forth for example are thos recommended in the following literature as adjuvants for pharmacy, cosmetic and relatedfields su'ch as in Ullmans Encyklopadie' der technischer Chemie,

V0 4 1953), pages'l to 39;Journal of Pharmaceutical 'Scien eesfV ol. 52 (1963), pages 9l8 et seqt; H. v.

Ciet sch Lindenwald, Hilfs toffe fur Pharmazi'e undangr e zende Gebiete; Pharm. Ind. Vol. 2 1961), pages 72 et seq., H, P L Fieldler, Lexicon der Hilfostoffe fur Pharmazie, Kosmetik und agrenz'ende Gebiete, Cantor Kg. Aulendorf i. Wurtt, 1971. j 1

Examples of such materials include gelatin, natural sugars such as sucrose or lactose, lecithin, pectin,

l off starch (for example corn starch); tylose, talc, lycopocially of plant origin (forexamplc. peanut oil, castor oil, olive oil, sesameoil, cottonseed oil, corn oil, monodiand triglycerides of saturated fatty acids (C H OL to C H O arid their mixtues, e.g., glyceryl 'monostearate, glyceryl distear'atej'glyceryl tristear'ate'; glyceryl trilaurate), pharmaceutically' compatible 'monoor polyvalent alcohols and polyglycols such as glycerine, mannitol, sorbitol, pentaeryth'ritol, ethyl 'alcohoL'diethylene glycol, triethylene glycol, ethylene glycol, ,pr'opy lene glycol.dipropylene'glycol, polyethylene glycol;- proylene glycol dipropylene glycol, polyethylene glycol 400 and other polyethylene'gly cols, as well mutant/1 tives of. such alcohols and polygly co'l s esters of satu rated, and. unsaturated fatty acids (2 to 22 carbon atoms, especially lOto l8 carbon atoms),i'with monol to 20 carbon atoms alkanol s) or polyhydric alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, mannitol, ethyl alcohol, butyl alco-' hol, octadecyl alcohol, etc.,'e.g.;glyceryl stearatc. glyceryl palmitate, glycol disteaarate, glycol dilau r ate, glycol diacetate, monoacetin, triacetin, glyceryl oleate, ethylene glycol stearate, such esters of polyvalent alcohols can be gi en case also be etherified, benzyl benzoate, dioxolanedglycerine formal, glycol furfural, dimethyl ac'etamide, lactimide, lactates, e.g., ethyl lactate, ethyl carbonate, silicones (especially middle viscosity dimethyl polysioloane) and the like:

For the production of solutions there can'. be used water or physiologically compatible'organi 'solvents, as for example, ethanol, l ,Z-prop yIene glycol, poly glycols, e.g., diethylene glycol, triethylene glycol and dipropylene glycol and their derivatives, dimethyl sulfox ide, fatty alcohols, e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and oleyl alcohol, triglycerides, e.g., glycoeryl acetate, partial estes of glycerine, e.g., monoacetic diacetin, glyceryl mo'nostearate, glyceryl distearate, glyceryl monopalrnitate, paraffins and the 1 i l '11. In, the productipn of th'epfepa'rations' thefe canbe used known and conventional solvent-aids. As solvent aids there can bej used, for example, polyoxyethy'lated fats, e.g'., polyoxyethylated ol eotriglyceride;linoliaed oleotriglyceride. Examples 'of"oleotriglycerides olive oil, peanut oil, ca'stor oil, sesame oil, cottonseed oil,c'or n oil see @1186 Dr. H. P; Fiedl'erf Lexikon der Halfsstoffe fur Pharmazie, Kosmetic jand' angren zende' Polyoxyethylated means tha't'the. materials qiues tion contain polyxyethylene chains whose degree of polymerization is generally between 2 and 40 and especially between lO and 20. Such materials can be obtained for example by reactionof thecorresponding glyceride with ethylene oxide (for example 40 moles of ethylene oxide per mole of glyceride).

Furthermore, there can be added preservatives, stabilizers, buffers, taste correctives, antioxidants and complex formers (for example ethylenediamine tetraacetic acid) and the like. In a given case for stabilization of the active molecule the pH is adjusted to about 3 to 7 with physiologically compatible acids or buffers. Generally, there is preferred as neutral as possible to weak acid (to pH 5) pH valueQAs antioxidants there can be used for example sodium meta bisulfite, ascorbic acid, gallic acid. alkyl gallates, e.g., methyl gallate and ethyl gallate, butyl hydroxyanisole, nordihydroguararetic acid,"tocopherols such as tocopherol and 17 synergists (material which bind heavy metals by com plex formation. for example, lecithin, ascorbicv acid,

phosphoric acid). The addition of synergists increases considerably the anti-oxidant activity of tocopherol, As

preservatives there can be used for example sorbic acid, p-hydroxybenzoie acid esters (for example lower alkyl esters such as the methyl ester and the ethyl ester benzoic acid), sodium benzoate, trichloroisobutyl alco- The compounds of the invention in the spasm test of Tedeschi (mouse) as well as in the motility test on the mouse in the circular cage of F. Heim show a good anxiolytic (tranquilizing) and calming activity.

This activity is comparable to the activity of the known medicine Diazcpoxide.

The lowest effective dosage in the above-mentioned animal experiments for example is 0.5 mg/kg body weight orally, 0.1 mg/kg sublingually and 0.05 mg/kg intravenously.

As a general dosage range there can be used, for example, 0.5 to l mg/kg body weight orally, 0.1 to 2 mg/kg sublingually and 0.05 to 1 mg/kg intravenously.

The compounds of the invention are useful in treating anxiety. stress and restlessness conditions, vegetative dystony, nervousness, irritability, moodiness, footlight fever (of actors), weather feelings, behaviour and adaptability problems of children, functional cardiovascular, gastrointestinal and respiratory complaints. They are also useful in' menstrual and climatic disturbances, aiding before operation and in assisting birth.

The pharmaceutical preparations generally contain between 1 and I07: of the active component (or components) of the invention.

The compounds can be delivered in the form of tablets, capsules, pills, dragees, suppositories, salves, gels, creams, powders, liquids, dusts or aerosols. As liquids there can be used oily or aqueous solutions or suspensions, emulsions. The preferred forms of use are as tablets which contain between I and 50 mg of active material or solutions which contain between 0.1 and of active material.

In individual doses the amount of active component of the invention can be used for example in an amount of:

a. in oral dispensation between l and 50 mg;

b. in parenteral dispensation (for example, intravenously, intramuscularly) between 0.1 and 5 mg;

0, in inhalation dispensation (solutions or aerosols) between 0.5 and 10 mg;

d. in rectal or vaginal dispensation between i and 50 (The dosages in each case are based on the free base).

r 18 For example, there is recommended the use of l to 3 tablets containing 1 to 50 mg of active ingredient 3 times dailyor for example intravenouslythe injection 1 to 3- times daily or for example intravenously the injection l to 3 times daily of a l to 2 ml ampoule con taining 01 to 10 mg of active substances. In oral preparations the minimum daily dosage for example is 3 mg;

the maximum daily dosage should not be over 200 mg.

In the treatment of dogs and cats the oral individual dosage in general is between 0.5 and 50 ,mg/kg body weight; the parenteral individual dosage is between about 0.1 and 10 ing/kg body weight. In the treatment of horses and cattle,'the individual dosage orally is generally between 5 and I00 mg/kg; the parenteral individualdosge is between l and ZOmg/kg body weight.

The acute toxicity of the co ounds ofthe invention inthe mouse (expressed by the Ll}, mg/kg method of vMiller and Tainter, Proc'. Soc. Expel Bio]. and Med, Vol. 57 (1944), pages 261, et seq.) in oral application is between 500 mg/kg 10,000fmg/kg (or .above 8000 mg/kg). H

The drugs can be used in human medicine in veterinary medicine} elgf, to treat cats, dogs,- horses, sheep, cattlegoats and pigs of inagriculture: The drugs can be used alone or'in admixture with otherpharmacologically active materials.

The salts can also be usedias curing agents for melamine-formaldehyde resins.

What is claimed is:

l. A compound of the formula:

wherein n is an integer from 1 to 4;

R is alkyl of l to 6 carbon atoms, a hydroxy group,

an amino group, an aloxy group having 1 to 6 carbon atoms, a phenyl group or a phenyl group substituted with alkyl of l to 6 carbon atoms, an alkoxy group of l to 6 carbon atoms, trifluoromethyl, fluorine or chlorine;

A is oxygen, sulfur, the imino group, or an alkylimino group having I to 6 carbon atoms, or when R is phenyl or substituted phenyl A also is two alkoxy groups having 1 to 6 carbon atoms or alkylenedioxy with 2 to 4 carbon atoms or C(R,)=A is the cyano group;

B is oxygen, sulfur, an imino group or an alkylimino group having 1 to 6 carbon atoms;

R is hydrogen, a hydroxy group, an alkyl group with l to 6 carbon atoms, an alkoxy group with l to 6 carbon atoms, or the group ()(CH. C(=A- l 1 N is nitrogen or an NO group; and

R and R are hydrogen, chlorine, fluorine, the trifluoromethyl group, alkyl groups of l to 6 carbon atoms or alkoxy groups with l to 6 carbon atoms, the tautomeric forms thereof and pharmaceutically acceptable salts thereof.,

2. A compound according to claim 1 wherein R is a hydroxy group, an amino group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenyl group substituted with alkyl of l to 6 carbon atoms, an alkoxy group of l to 6 carbon atoms, trifluoromethyl, fluorine or chlorine.

3. A compound according to claim 1 wherein A and B are both oxygen, R is hydrogen, a hydroxy group or an alkoxy group with l to 4 carbon atoms, R, is hydrogen, chlorine or fluorine, R is hydrogen and R is alkyl of l to 6 carbon atoms, a hydroxy group, an alkoxy group with l to 6 carbon atoms, a phenyl group or a fluorophenyl, methylphenyl or methoxyphenyl.

5. A compound according to claim 4 wherein n is l or 2.

6. A compound according to claim 3 wherein n is l or 2.

7. A compound according to claim 1 wherein n is l or 2.

8. A compound according to claim 1 wherein the group C(R )=A is cyano, B is oxygen, R is hydrogen, hydroxy or alkoxy with l to 4 carbon atoms, R is hydrogen, chlorine or fluorine, and R is hydrogen.

9. A compound according to claim 8 wherein R2 is hydrogen, hydroxy, methoxy, ethoxy or propoxy.

10. A compound according to claim 9 wherein n is l 11. A compound according or 2.

12. A compound according to claim 1 wherein n is an integer from 1 to 3, R is methyl, hydroxy, ethoxy, phenyl 'or chlorophenyl,

A is oxygen or C(R, )=A is cyano,

B is oxygen,

R2 is hydrogen,

R is hydrogen or chloro, and

R hydrogen.

to claim 8 wherein n is l 

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 wherein R1 is a hydroxy group, an amino group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenyl group substituted with alkyl of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, trifluoromethyl, fluorine or chlorine.
 3. A compound according to claim 1 wherein A and B are both oxygen, R2 is hydrogen, a hydroxy group or an alkoxy group with 1 to 4 carbon atoms, R3 is hydrogen, chlorine or fluorine, R4 is hydrogen and R1 is alkyl of 1 to 6 carbon atoms, a hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a phenyl group or a phenyl group substituted with chlorine, fluorine, a trifluoromethyl group, an alkyl group of 1 to 4 carbon atoms or an alkoxy group of 1 to 4 carbon atoms.
 4. A compound according to claim 3 wherein R2 is hydrogen, hydroxy, methoxy, ethoxy propoxy and R1 is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, hydroxy, phenyl, chlorphenyl, fluorophenyl, trifluorophenyl, methylphenyl or methoxyphenyl.
 5. A compound according to claim 4 wherein n is 1 or
 2. 6. A compound according to claim 3 wherein n is 1 or
 2. 7. A compound according to claim 1 wherein n is 1 or
 2. 8. A COMPOUND ACCORDING TO CLAIM 1 WHEREIN THE GROUP C(R1)=A IS CYANO, B IS OXYGEN, R2 IS HYDROGEN HYDROXY OR ALKOXY WITH 1 TO 4 CARBON ATOMS, R3 IS HYDROGEN, CHLORINE OR FLUORINE, AND R4 IS HYDROGEN.
 9. A compound according to claim 8 wherein R2 is hydrogen, hydroxy, methoxy, ethoxy or propoxy.
 10. A compound according to claim 9 wherein n is 1 or
 2. 11. A compound according to claim 8 wherein n is 1 or
 2. 12. A compound according to claim 1 wherein n is an integer from 1 to 3, R1 is methyl, hydroxy, ethoxy, phenyl or chlorophenyl, A is oxygen or -C(R1) A is cyano, B is oxygen, R2 is hydrogen, R3 is hydrogen or chloro, and R4 hydrogen. 